University of Groningen
Presentation and treatment of biliary atresia Witt, Mauri
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Witt, M. (2018). Presentation and treatment of biliary atresia. Rijksuniversiteit Groningen.
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Summary, general discussion
and future perspectives
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SUMMARY, GENERAL DISCUSSION AND FUTURE PERSPECTIVES.
The development of surgical restoration of bile flow via the Kasai porto-enterostomy (KPE) has greatly improved the prognosis of patients with biliary atresia (BA). Despite the development of KPE, the majority of patients with biliary atresia still need a liver transplantation (LTx) at child age.1-3 Biliary atresia still
carries a significant morbidity and even mortality, which underlines the need of detailed analysis to further improve the prognosis of these patients. This thesis describes several studies in which different aspects of the current treatment of patients with biliary atresia has been investigated. The aim of this thesis was to
assess the results of current strategies to diagnose and treat biliary atresia and to determine targets for improvement in the chain of care. We used an extensive
nationwide database of all BA patients since 1987, which allowed to study in great detail the diagnostic, therapeutic and follow-up processes of patients with BA in the Netherlands. Based on the analyses, described in different chapters, we could identify several areas of improvement in the diagnostic, the therapeutic and the follow-up processes. The present general discussion offers a reflection on the main results of this thesis and several future perspectives for the care of patients with biliary atresia.
The chance of clinical success of KPE is largely determined by the age at which the surgery is performed: the prognosis is better if surgery is performed before the age of 60 days.4-11 However, the percentage of patients undergoing Kasai before
60 days of age in our country is relatively low and has not increased over the past decade. Almost half of the patients are still operated beyond the age of 60 days.
In chapter 2 we showed that insufficient recognition of early symptoms of biliary
atresia, such as acholic stools, might be an underlying contributor to this delay. Neither parents nor youth health care professionals nor general practitioners were able to recognise acholic stools reliably. Two-third of all parents and youth health care professionals and only one-third of the general practitioners recognised all acholic stool samples. To prevent delay in the diagnosis of BA due to insufficient recognition of acholic stool by parents and primary healthcare professionals a screening tool for acholic stool would seem desirable. In several countries the Infant Stool Colour card (ISCC) or Taiwan Stool Colour Card has been implemented successfully with remarkably improved outcomes of patients with BA.5,10,12-14 Our
study confirms that the ISCC is a sensitive and specific screening tool for acholic stools and significantly improves parents’ recognition of acholic stools. This cheap and simple screening tool might also be a useful adjunct for primary healthcare professionals. Since the routine health check at the age of four weeks would be an optimal time for identification of BA, we are currently cooperating with the Dutch youth healthcare clinics to implement the ISCC by adding it to the child health booklet.
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Apart from the implementation of the classic “paper” ISCC we are currently developing a smartphone application as a screening tool for acholic stool. Since an estimated ~90% of all Dutch people use a smartphone, this seems to be an excellent device to use for a screening program. Our application provides information about BA and the importance of early detection of acholic stools and contains software to analyse the stool colour. A photograph of the infants’ stool colour can be taken with the smartphone’s camera and the application will analyse the stool colour and alert parents when further investigation is recommended. This application is expected to be available in the App store (iPhone) and play store (Android) shortly. Besides jaundice and acholic stools, vitamin K deficiency bleeding (VKDB) is another common presenting symptom of patients with BA in the Netherlands. A previous analysis of our NeSBAR database showed that the Dutch vitamin K prophylactic regimen of a single oral dose of 1 mg vitamin K at birth, followed by a daily oral dose of 25 µg did not sufficiently prevent VKDB in breastfed infants with still unrecognised BA.15 More than 80% of these infants presented with VKDB.15
The risk of VKDB in Dutch breastfed infants with BA was eight to ten times higher than that of Danish BA patients on either a weekly oral dose of 1 mg vitamin K or a single IM dose of 1 mg vitamin K at birth.15 Based on these observations, the Dutch
prophylactic regimen has been adapted since March 2011. The recommended daily oral dose of 25 µg vitamin K was increased to 150 µg daily for all breasted infants. In chapter 3 we evaluated the preventive effect of the adapted Dutch guideline with respect to the incidence of VKDB as a presenting symptom in breastfed BA patients. Our data show that the new Dutch prophylactic regimen still fails to prevent VKDB in breastfed infants with unrecognised BA, in contrast to the Danish regimen consisting of a single intramuscular dose of 1 mg of vitamin K at birth. VKDB still occurred in 82% of these patients and included several cases of intracranial haemorrhage. The risk of VKDB in breastfed infants with BA on a daily oral dose of 150 µg vitamin K was 20-fold higher than on a single intramuscular dose at birth. Based on our results, the Health Council of the Netherlands recently recommended adaption of the Dutch guideline towards a regimen of a single intramuscular dose of 1 mg of vitamin K at birth for all breastfed infants.16 Currently,
the Ministry of Health is evaluating this advice and is expected to make a decision on the implementation of a new guideline.
As stated above, the Dutch prophylactic regimen has led to a relatively high number of BA patients with a VKDB at the time of diagnosis. It has remained unclear, however, whether the VKDB affected the short- or long-term prognosis of these patients. In chapter 4 we analysed whether VKDB at initial presentation of patients with BA affects their prognosis after KPE. Regarding short-term outcome there were no differences between BA patients with and without VKDB at initial presentation.
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However, a higher percentage of patients with VKDB required LTx during follow-up compared with patients without VKDB, 70% versus 54% respectively.
Neither the age at LTx nor the pre-transplant mortality or NLS significantly differed between patients with VKDB and patients without VKDB. Although we analysed a large cohort of BA patients, our study might not have had enough patients and follow-up to address discrete differences with statistical significance. Interpretation of the Kaplan Meier curve may suggest a difference in NLS showing a disadvantage for children with VKDB. We cannot exclude that a larger patient population or longer follow-up would have led to slightly different conclusions. Nevertheless, our present data will be helpful to provide relevant prognostic information to parents of patients with BA. Furthermore, we showed previously that pre-transplant mortality for BA in our country was very high; 26% between 1987 and 1996 and 16% between 1997 and 2008,17 which was a strong motivator
for the current centralised BA care in The Netherlands. However, our study shows that waiting list mortality in the whole cohort is still 12%. Recently, Eurotransplant Registry data of BA patients between zero and five years from five countries showed a waiting list mortality of 7.9% within two years after listing.18 Although
the waiting list mortality in our country tended to decrease over the past decades, it is still considerable. Therefore, early referral for LTx screening and increasing the availability of (living-related) donors are still relevant issues to improve the prognosis of patients with biliary atresia.
As stated, despite Kasai surgery, liver fibrosis often progresses in patients with BA, resulting in cirrhosis and the development of portal hypertension. A well-known complication of portal hypertension is bleeding from oesophageal varices (EV). In
chapter 5 we investigated the incidence and severity of EV bleeding in BA patients
after KPE. Our data suggest that a quarter of all BA patients undergoing KPE will develop EV bleeding. However, major complications affecting the prognosis of these patients did not occur. Despite a relatively high incidence of EV bleeding, the absolute number of patients with EV bleeding in our cohort was low. Therefore, it was not possible to construct a proper prediction model for EV bleeding. Other studies suggested the varices prediction rule (VPR), derived from albumin and platelet levels, as a promising novel predictor of EV in BA patients.19,20 Our data
also showed a significantly lower VPR in the patients with EV bleeding. We suggest that the VPR could be useful in identifying those patients who are at highest risk of EV bleeding and therefore eligible for endoscopic screening. This should, however, be studied in larger prospective cohorts. Given the absence of major complications of EV bleeds in our patients, our data do not support the concept of routine early-on endoscopic screening of all BA patients.
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If liver fibrosis progresses and cirrhosis occurs, LTx is the only lifesaving option. Most patients with BA need LTx during childhood, and 40-50% of the patients even do so before the age of two years.3,21 LTx for BA after the age of two years
can still be indicated, but the need seems far less frequent.18 Reaching the age
of two years with native liver could therefore mark an important mile stone and positive prognostic factor for patients with BA. In chapter 6 we assessed the long-term prognosis of BA patients who have reached the age of two years with their native liver (and where not listed for liver transplantation at the age of two years). Our analysis indicated that indeed almost 90% of patients with two-year native liver survival (NLS) reach adulthood, and over half of all patients do so with their native liver. Our data thereby indeed confirm the hypothesis, that reaching NLS at the age of two years is a milestone for patients with BA, which marks a generally good prognosis for reaching adulthood. Nevertheless, we must realise that a significant fraction of patients who, after having survived the first two years with native liver, seem to be out of danger ultimately still do need an LTx as a result of their underlying pathology, once again underlining the severity of BA. We could not identify parameters, other than clearance of jaundice, apparent before the age of two years that had a significant effect on continued NLS after two years of age. Other predictors, such as the role of gut dysbiosis, impaired gut wall integrity, on-going cytomegalovirus infection at time of the KPE and biochemical and clinical characteristics at the age of two years should be studied in the future. Unfortunately, these data were not available in our retrospective study. Irreversible jaundice or the development of portal hypertension were the main indications for LTx in those patients who survived at least two years with their native liver and needed a transplant prior to the second decade of life.
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CONCLUSIONS AND FUTURE PERSPECTIVES
In the past decades, impressive improvements in the various elements of the chain of care of BA patients have been made. In order to further improve the outcome of BA patients in the Netherlands, the treatment of these patients has been centralised since 2012 and a multidisciplinary KPE team consisting of a paediatric surgeon, hepatobiliary/transplant surgeon and paediatric transplant hepatologist has been introduced. To prevent late referrals in children with insufficient clinical response after KPE we have designed a follow-up schedule with clear cut-off points for referral to the expertise centre with experience in BA care and paediatric LTx. During follow-up patients are regularly seen in the BA expertise centre and, in addition, we have now installed protocol visits to the liver transplantation team during follow-up. Also, since 2002 the living related LTx-program has been introduced, which is associated with better disease outcome.22,23 In this thesis, we
did not analyse the difference in outcome between patients treated before and after centralisation. Follow-up is still too short to perform a thorough analysis of NLS after centralisation. Based on results from other countries it is expected that centralisation of BA treatment results in better short- and long-term outcome of patients with BA.21,24-26 The results of centralisation of BA care in our country
should be studied in the future.
Almost half of our patients are still operated after the age of 60 days. Implementation of the ISCC and the stool colour application in the Netherlands might lead to earlier diagnosis, referral and treatment of BA and thereby to significantly improved outcomes. We also showed that the new Dutch prophylactic regimen still fails to prevent VKDB in breastfed infants with unrecognised BA, which is associated with high morbidity and mortality. Therefore, we support the advice of the Health Council of the Netherlands to adapt the Dutch guideline towards a regimen of a single intramuscular dose of 1 mg of vitamin K at birth for all breastfed infants. The rapid implementation of this new guideline is expected to significantly decrease VKDB as a presenting symptom in BA patients in the Netherlands.
Our data showed that a quarter of all BA patients will develop EV bleeding. Two-thirds of these patients were already listed for LTx. Further studies of the VPR or other predictive variables to identify those patients who are at highest risk for EV bleeding and might need endoscopic screening should be conducted. Not only morbidity on the waiting list for LTx was high, but also (still) waiting list mortality. Although waiting list mortality in The Netherlands had decreased over the past decades, it is still considerable. Hopefully, after centralisation of BA care, the implementation of a clear follow-up schedule and the further development of the living-related LTx program, this waiting list mortality will further decrease in the future.
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In conclusion, a long-term, nationwide registry on biliary atresia has offered important insights into the care of this rare disease and on areas of improvement. In the Netherlands, several measures based on these insights have been taken to improve the outcome for children with BA and for other children with neonatal cholestatic syndromes (changing the Vitamin K prophylaxis is also expected to benefit patients with yet unrecognised other forms of neonatal cholestasis). In the past decades, the care for patients with BA in our country has improved considerably. Nevertheless, this thesis shows that there is still room for further improvement. Due to the rarity of the disease, even with nationwide databases, insufficient numbers of patients to address clinical questions with sufficient statistical resolution remains a fundamental problem. Several countries have created national databases with clinical data of BA patients. International collaboration and combining these datasets will be necessary to answer important clinical issues concerning BA and to establish benchmarks for the care of BA patients. The recent European Union initiative to establish European Reference Networks provides hope for the future in this respect. The Dutch Expertise Center for Biliary Atresia, based in the University Medical Center Groningen, is part of this initiative as member of the European Reference Network–RARE LIVER (www.rare-liver.eu). It is expected that combining national or multicentre databases will allow to identify areas of further improvement with a higher resolution.
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